P524: PHASE 1B/2 STUDY ON SAFETY, PK, PD, AND PRELIMINARY EFFICACY OF THE SELECTIVE SYK INHIBITOR LANRAPLENIB IN COMBINATION WITH THE FLT3 INHIBITOR GILTERITINIB, IN FLT3-MUTATED R/R AML (KB-LANRA 1001)
Authors: E. M. Stein, A. Patel, L. C. Michaelis, G. Schiller, R. Swords, L. A. Carvajal, G. Bray, J. DiMartino, M. Y. Levy
Journal: HemaSphere (2022)

Background: Spleen tyrosine kinase (SYK) is a key driver of lymphoid and myeloid cell signaling pathways and has been implicated in the pathogenesis of acute myeloid leukemias (AML) defined by dysregulated expression of HOXA9 and MEIS1 transcription factors. SYK also cooperates with internal tandem duplication (ITD)-mutated FMS-like tyrosine kinase 3 (FLT3) to drive leukemogenesis. Combined pharmacologic inhibition of SYK and FLT3 results in robust antileukemic effects in preclinical models of FLT3 ITD-driven AML. Lanraplenib (LANRA) is an oral, selective SYK inhibitor. Studies demonstrate dose-dependent reductions in viability of leukemic cells ex vivo from newly diagnosed FLT3 ITD-mutated AML patients (pts) as well as additive reductions in viability when combined with the selective FLT3 inhibitor, gilteritinib. Once daily (QD) LANRA was well-tolerated at doses up to 50mg for 7 days and 30mg for up to 12 weeks in healthy volunteers and pts with autoimmune disorders. Aims: The KB-LANRA 1001 trial will investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of LANRA when combined with gilteritinib in relapsed or refractory pts with FLT3-mutated AML. We will also evaluate the rate of complete responses (CR) and CR with partial hematologic recovery (CRh), duration of response (DoR), event-free (EFS) and overall survival (OS). Methods: KB-LANRA 1001 is a global, multicenter trial of LANRA in combination with standard dose gilteritinib (120mg QD) in FLT3-mutated AML pts aged ≥18 with at least 1 prior therapy. Those who have been treated with midostaurin or other multikinase inhibitors are eligible, though pts who failed to achieve at least a partial response or who relapsed following prior exposure to gilteritinib or other next-generation FLT3 inhibitor monotherapy are excluded. Both medications will be administered daily in sequential, 28-day cycles until progression/relapse, intolerance, or failure to achieve at least a partial remission after 6 cycles. The Phase 1b component will define the maximum tolerated and/or recommended Phase 2 dose (MTD/RP2D) of LANRA when added to gilteritinib in accordance with a 3 + 3 dose escalation design. PK and PD parameters will be characterized for LANRA monotherapy and when co-administered with gilteritinib. Four LANRA doses are planned for evaluation (20, 40, 60 and 90mg). All decisions regarding dose escalation including declaration of the MTD will be made by a dose-escalation committee based on the prospectively defined definition of dose-limiting toxicities and other safety metrics. The Phase 2 component will further evaluate safety, PK, PD and preliminary efficacy of the combination at the LANRA RP2D. For both trial components, response assessments will be conducted on Day 1 of Cycles 2 and 3 and every 3 cycles thereafter until 2 consecutive assessments indicate CR or CRh. A 2-stage design will be employed to test the null hypothesis that the rate of CR/CRh for the combination is ≤23%, as reported for gilteritinib monotherapy, versus the alternative hypothesis of CR/CRh ≥46%, among pts treated at the LANRA RP2D. All pts will be followed for relapse, EFS and OS. Key exploratory endpoints will be assessments of measurable residual disease among pts who achieve CR/CRh, correlations with selected baseline biomarkers that may predict efficacy outcomes and assessment of LANRA PD properties (including target engagement) when administered alone and in combination with gilteritinib. Results: Trial in progress. Summary/Conclusion: Accrual is ongoing.